Two tightly linked common intronic variants of the Lysosomal Acid Lipase (LIPA) locus, present in nearly one- third of the population, have been shown to increase the risk of coronary artery disease (CAD) by 13-17% in large-scale genome-wide association studies. LIPA mediates the hydrolysis of cholesteryl esters and patients with rare loss-of-function mutations develop hypercholesterolemia and CAD. However, these common LIPA variants are intronic, not associated with lipid abnormalities, and result in increased LIPA transcripts in monocytes, a constellation of findings that has prevented further mechanistic understanding. We have discovered a previously unrecognized coding variant in close linkage with the intronic variants that is equally associated with CAD risk. We hypothesize that the coding variant, with potential consequences to LIPA enzyme activity and cellular cholesterol homeostasis, is the culprit link with cardiovascular disease. This concept will be evaluated by assessing the effect of the coding variant on levels of LIPA mRNA, protein, and enzyme activity in circulating monocytes isolated from cohorts of patients with and without known CAD. In order to definitely implicate the coding variant, induced pluripotent stem cell derived monocytes/macrophages harboring the coding variant in the absence of the confounding intronic variants will be studied. This model will allow determination of whether the coding variant in isolation alters LIPA mRNA, protein, and enzyme activity. Further mechanistic characterization will include effects on crucial lipid metabolic phenotypes implicated in CAD pathogenesis including cholesterol efflux, lipid uptake, and foam cell formation. Finally, given that the coding variant lies in the signal peptide region of LIPA, its impact on LIPA trafficking, maturation, and secretion will be assessed as potential mechanisms for dysfunction. Taken together, this highly translational set of experiments will provide the first mechanistic insight ito an important genetic risk allele associated with CAD.